Benzoylecgonine, ecgonine and ecgonidine derivatives

ABSTRACT

The present invention relates to a novel class of covalently coupled benzoylecgonine, ecgonine and ecgonidine derivatives that are useful for alleviating the symptoms of immunoregulatory disorders, neuromuscular disorders, joint disorders, connective tissue disorders, circulatory disorders and pain. Accordingly, this invention also relates to pharmaceutical compositions and methods for their use.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a novel class of covalentlycoupled benzoylecgonine, ecgonine and ecgonidine derivatives that areuseful for alleviating the symptoms of immunoregulatory disorders,neuromuscular disorders, joint disorders, connective tissue disorders,circulatory disorders and pain. Accordingly, this invention also relatesto pharmaceutical compositions and methods for their use.

BACKGROUND OF THE INVENTION

[0002] Benzoylecgonine, ecgonine and ecgonidine are known metabolites ofcocaine (see, for example, S. M. Roberts et al., “An Assay forCocaethylene and Other Cocaine Metabolites in Liver UsingHigh-Performance Liquid Chromatography”, Anal. Biochem., 202, pp. 256-61(1992), D. T. Chia and J. A. Gere, “Rapid Drug Screening Using Toxi-LabExtraction Followed by Capillary Gas Chromatography/Mass Spectroscopy”,Clin. Biochem., 20, pp. 303-06 (1987)). Routes for their preparationhave been established (see, for example, A. H. Lewin et al.,“2β-Substituted Analogues of Cocaine. Synthesis and Binding to theCocaine Receptor”, J. Med. Chem., 35, pp. 135-40 (1992); M. R. Bell andS. Archer, “L(+)-2-Tropinone”, J. Amer. Chem. Soc., 82, pp. 4642-44(1960)).

[0003] We have demonstrated the pharmaceutical efficacy ofbenzoylecgonine and ecgonine in the treatment of rheumatoid arthritis,osteoarthritis and related inflammatory disorders (see, for example,U.S. Pat. Nos. 4,469,700, 4,512,996 and 4,556,663). We have alsodemonstrated the pharmaceutical efficacy of certain 2-β-derivatizedanalogues of benzoylecgonine, ecgonine and ecgonidine (see, for example,co-pending U.S. patent application Ser. No. 07/999,307). We have nowdiscovered a new class of easily synthesized, covalently coupledbenzoylecgonine, ecgonine and ecgonidine derivatives that have noveltherapeutic features and improve certain therapeutic properties ofunderivatized benzoylecgonine, ecgonine and ecgonidine.

SUMMARY OF THE INVENTION

[0004] It is a principal object of this invention to provide easilysynthesized, covalently linked benzoylecgonine, ecgonine and ecgonidinederivatives which are useful for alleviating the symptoms ofimmunoregulatory disorders, neuromuscular disorders, joint disorders,connective tissue disorders, circulatory disorders and pain.

[0005] The benzoylecgonine, ecgonine and ecgonidine derivatives of thisinvention are represented by formulas I and II, respectively:

[0006] wherein:

[0007] each R¹ is independently selected from the group consisting of H;COR²; COBn; alkyl; alkenyl; and alkynyl, said alkyl, alkenyl and alkynylbeing optionally substituted with OH, SH, NH₂, CN, CF₃ or halogen;

[0008] A is -L—(M)p;

[0009] B is -L—(M′)p,;

[0010] each p and p′ is independently selected from the group consistingof 1 or 2;

[0011] each L is independently a linker which,

[0012] (a) if linking one M or M′ to the ring system, is selected fromthe group consisting of —(CR²R²)_(n)—CO—Q—; —(CR²R²)_(n)—Q—CO—;—(CR²R²)_(n)—O—C(OH)—; and —(CR²R²)_(n)—Q—; or

[0013] (b) if linking two M or M′, the same or different, to the ringsystem is

[0014] (c) if linking two ring systems chosen from compounds of formulasI and II, the same or different, to M or M′ is

[0015] each n is independently selected from the group consisting of 0,1, 2 and 3;

[0016] each Q is independently selected from the group consisting of—NH—, —O— and —S—;

[0017] each M and M′ is independently a moiety that, either alone or incombination with other M or M′ moieties, enhance the distributioncharacteristics, intrinsic activity or efficacy of said compound,provided that M is not a moiety having the formula CH₂—CHX—R³ when B is—O—CO—M′, —O—M′ or when B is not present (i.e., in compounds of formulaII);

[0018] each R² is independently selected from the group consisting of H;alkyl; alkenyl; alknyl; alkoxy; aminoalkyl; haloalkyl; aryl;heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl; halogen; aroyl,acyl; and aralkyl; any of said R² being optionally substituted with OH,SH, NH₂, oxo and halogen;

[0019] X is selected from the group consisting of OH; SH; NH₂; andhalogen; and

[0020] R³ is selected from the group consisting of alkyl, alkenyl andalkynyl, optionally substituted with OH, SH, NH₂ or halogen; COCH₃;COPh; and COBn.

[0021] It is a further object of this invention to providepharmaceutical compositions comprising compounds of formulas I and II,and mixtures thereof.

[0022] It is also an object of this invention to provide methods foralleviating the symptoms of immunoregulatory disorders, neuromusculardisorders, joint disorders, connective tissue disorders, circulatorydisorders and pain using the compounds and pharmaceutical compositionsdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION

[0023] In accordance with this invention, the following definitionsapply:

[0024] The following abbreviations are used herein:

[0025] Bn=benzyl radical; and Ph=phenyl radical.

[0026] The term “alkyl”, alone or in combination, refers to a straightchain or branched chain alkyl radical having from one to ten, preferablyfrom one to six, carbon atoms. Examples of such alkyl groups are methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl andisohexyl.

[0027] The terms “alkenyl” and “alkynyl”, alone or in combination, referto a straight chain or branched chain alkenyl or alkynyl radical,respectively, having from two to ten, preferably from two to six, carbonatoms. The alkenyl radicals can be in the cis, trans, E- or Z-form.Examples of such alkenyl radicals are vinyl, ethenyl, propenyl and1,4-butadienyl. Examples of alkyl radicals are ethynyl and propynyl.

[0028] The term “alkoxy”, alone or in combination, refers to an alkylether radical, wherein alkyl is defined as above. Examples of suchalkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy andtert-butoxy.

[0029] The terms “aralkyl”, “aminoalkyl” and “haloalkyl”, alone or incombination, refer to an alkyl radical as defined above wherein onehydrogen atom is replaced by an aryl radical, an amino radical or ahalogen radical, respectively. The aryl, amino or halogen radical may belocated on the terminal carbon or an internal carbon of the alkylradical.

[0030] The term “aryl”, alone or in combination, refers to a phenyl ornaphthyl radical optionally substituted with one or more substituentsselected from the group consisting of alkyl, alkoxy, halogen, hydroxy,amino, nitro, cyano and haloalkyl. The aryl radical may be attachedthrough any member of the ring that results in the creation of a stablestructure. Examples of such aryl radicals include tolyl, xylyl, cymyl,mesityl and phenyl. The most preferred aryls are phenyl and phenylsubstituted with alkyl having from one to five carbon atoms.

[0031] The term “aroyl” refers to an acyl radical derived from anaromatic carboxylic acid. Examples of such aroyl radicals includeoptionally substituted benzoic acid and naphthoic acid, such as benzoyl,4-chlorobenzoyl, 4-carboxybenzoyl, 4-benyloxycarbonyl)benzoyl,1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl and 3-hydroxy-2-naphthoyl.

[0032] The terms “benzoylecgonine compound”, “ecgonine compound” and“ecgonidine compound” refer not only to those compounds, but also to thecorresponding 2-β derivatized analogs (such as the corresponding 2-βacids and 2-β alcohols) of benzoylecgonine, ecgonine, ecgonidine and thecompounds of formulas I and II. For example, the 2-β acid of a compoundof formula II will be referred to herein as an ecgonidine compound.

[0033] The term “acyl” refers to an alkyl radical as defined abovelinked via a carbonyl.

[0034] The term “cycloalkyl”, alone or in combination, refers to amonocyclic, bicyclic or tricyclic alkyl radical, wherein each cyclicmoiety contains from about three to about eight carbon atoms. Examplesof such cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

[0035] The term “cycloalkylalkyl” refers to an alkyl radical as definedabove which is substituted with a cycloalkyl radical containing fromabout three to about eight carbon atoms.

[0036] The term “distribution characteristics” refers to the ability ofa molecule to reach a targeted site. The distribution characteristics ofthe compounds of formulas I and II may be assayed by following theprotocols set forth in, for example, A. Leo et al., “PartitionCoefficients and Their Uses”, Chemical Reviews, 71, p. 535 (1971) and C.Hansch, “Linear Relationships Between Lipophilic Activity and BiologicalActivity of Drugs”, J. Pharm. Sci., 61, p. 1 (1972).

[0037] The term “halogen” refers to fluorine, chlorine, bromine oriodine.

[0038] The term “heterocyclyl” refers to a stable 5-7 memberedmonocycle, 8-11 membered bicyclic heterocycle radical or an 8-16membered tricyclic heterocycle which is may be saturated,mono-unsaturated or polyunsaturated, and which may be optionallybenzofused if monocyclic. This term refers to both aromatic andnon-aromatic heterocycles. Each heterocycle consists of carbon atoms andfrom one to four heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. As used herein, the terms “nitrogen andsulfur heteroatoms” include nitrogen and sulfur in any of theiroxidation states, and the quaternized form of any basic nitrogen. Theheterocyclyl radical may be attached through any atom of the cycle whichresults in the creation of a stable structure. Preferred heterocyclylgroups include, for example, benzimidazolyl, imidazolyl, imidazolinoyl,imidazolidinyl, quinolyl, isoquinolyl, indolyl, pyridyl, pyrrolyl,pyrrolinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, morpholinyl,thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, tetrazolyl,thiazolidinyl, benzofuanoyl, thiamorpholinyl sulfone, benzoxazolyl,oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl,tetrahydropyranyl, tetrahydrofluranyl, thiadiazoyl, benzodioxolyl,thiophenyl, tetrahydrothiophenyl and sulfolanyl.

[0039] The term “intrinsic activity or efficacy” refers to activity of amolecule with respect to alleviating the symptoms of immunoregulatorydisorders, neuromuscular disorders, joint disorders, connective tissuedisorders, circulatory disorders and pain. Intrinsic activity orefficacy may be associated with the interaction of that molecule withits targeted receptor. Intrinsic activity or efficacy of the compoundsof formulas I and II may be assayed by following the procedure set forthin, for example, A. J. Clark, J. Physiol., 61, p. 547 (1926); J. H.Gaddum, J. Physiol., 61, p. 141 (1926); J. H. Gaddum, J. Physiol., 89,p. 7p (1937); E. J. Ariens and A. M. Simonis, J. Pharm. Pharmacol., 16,p. 289 (1964); or R. P. Stevenson, Br. J. Pharmacol., 11, p. 379 (1956).Particularly relevant are the in vivo rat procedures outlined in the CRCHandbook of Animal Models for the Rheumatic Diseases, R. A. Greenwaldand H. S. Diamond, eds., CRC Press (Boca Raton, Fla.) (1988)

[0040] The term “optionally substituted” refers to the substitution, ifat all, of one or more hydrogen atoms in the unsubstituted moiety whichresults in the formation of a stable compound. Preferably, the moiety issubstituted, if at all, at one to three positions. More preferably, themoiety is substituted, if at all, at only one position.

[0041] The term “pharmaceutically effective amount” refers to an amounteffective to alleviate the symptoms of immunoregulatory disorders,neuromuscular disorders, joint disorders, connective tissue disorders,circulatory disorders and pain in a mammal, including a human.

[0042] The term “pharmaceutically acceptable carrier or adjuvant” refersto a carrier or adjuvant that may be administered to a mammal, includinga human, together with a compound, mixture, or composition of thisinvention which is non-toxic and does not destroy the pharmacologicalactivity of the compound, mixture or composition of this invention.

[0043] The term “ring system” refers to the radical of the correspondingcyclic moiety to which a given substituent is attached. For example, thering system for compounds of formulas I and II is that portion of thosecompounds to which the substituents R¹, A and B are attached. The“aromatic ring system of any conventional anti-inflammatory or analgesicagent” refers to that portion of a known anti-inflammatory or analgesiccompound that contains an aromatic ring system and which, when linked tothe benzoylecgonine, ecgonine or ecgonidine portion of the compounds ofthis invention, results in the formation of a stable covalently coupledmolecule. Preferred conventional anti-inflammatory and analgesic agentsfor use in the covalently coupled derivatives of this invention include,but are not limited to alkyl and aryl esters, salts and amides ofsalicylic acid (such as sodium salicylate, sodium thiosalicylate,magnesium salicylate, choline salicylate, carbethyl salicylate, phenolsalicylate, salicylamide, aspirin (acetylsalicylic acid), aluminumaspirin, calcium acetylsalicylate, salsalate and flufenisal),N-arylanthranilic acids (such as mefenamic acid and meclofenamatesodium), arylacetic acid derivatives (such as indomethacin, sulindac,tolmetin, zomepirac, ibuprofen, naproxen, fenoprofen and piroxicam).More preferred conventional anti-inflammatory and analgesic agents foruse in the covalently coupled derivatives of this invention are aspirin,naproxen and ibuprofen. We prefer coupling these conventionalanti-inflammatory and analgesic agents to the free acid form ofbenzoylecgonine or ecgonine.

[0044] The covalently coupled benzoylecgonine, ecgonine and ecgonidinederivatives of this invention are represented by formulas I and II,respectively:

[0045] wherein:

[0046] each R¹ is independently selected from the group consisting of H;COR²; COBn; alkyl; alkenyl; and alkynyl, said alkyl, alkenyl and alkynylbeing optionally substituted with OH, SH, NH₂, CN, CF₃ or halogen;

[0047] A is -L—(M)p;

[0048] B is -L—(M′)p;

[0049] each p and p′ is independently selected from the group consistingof 1 or 2;

[0050] each L is independently a linker which,

[0051] (a) if linking one M or M′ to the ring system, is selected fromthe group consisting of —(CR²R²)_(n)—CO—Q—; —(CR²R²)_(n)—Q—CO—;—(CR²R²)_(n)—O—C(OH)—; and —(CR²R²)_(n)—Q—; or

[0052] (b) if linking two M or M′, the same or different, to the ringsystem is

[0053] (c) if linking two ring systems chosen from compounds of formulasI and II, the same or different, to M or M′ is

[0054] each n is independently selected from the group consisting of 0,1, 2 and 3;

[0055] each Q is independently selected from the group consisting of—NH—, —O— and —S—;

[0056] each M and M′ is independently a moiety that, either alone or incombination with other M or M′ moieties, enhance the distributioncharacteristics, intrinsic activity or efficacy of said compound,provided that M is not a moiety having the formula —CH₂—CHX—R³ when B is—O—CO—M′, —O—M′ or when B is not present (i.e., in compounds of formulaII);

[0057] each R² is independently selected from the group consisting of H;alkyl; alkenyl; alkynyl; alkoxy; aminoalkyl; haloalkyl; aryl;heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl; halogen; aroyl,acyl; and aralkyl; any of said R² being optionally substituted with OH,SH, NH₂, oxo and halogen;

[0058] X is selected from the group consisting of OH; SH; NH₂; andhalogen; and

[0059] R³ is selected from the group consisting of alkyl, alkenyl andalkynyl, optionally substituted with OH, SH, NH₂ or halogen; COCH₃;COPh; and COBn.

[0060] Preferred compounds of formulas I and II are those wherein Q is—O—; M′ is selected from the group consisting of —OH, O—(CH₂)_(n)-aryland O—C(O)-aryl; and n is selected from the group consisting of 0 and 1.

[0061] Other preferred compounds of formulas I and II are those whereinA or B or both are independently selected from the group consisting of—(CR²R²)_(n)—O—CO—(CR²R²)_(n)-E , —(CR²R²)_(n)—CO—O—(CR²R²)_(n)-E,—(CR²R²)_(n)—O—CH(OH)—(CR²R²)_(n)-E and —(CR²R²)_(n)—O—(CR²R²)_(n)-E,wherein:

[0062] each R² is independently selected from the group consisting of H;alkyl; alkenyl; alkynyl; alkoxy; aminoalkyl; haloalkyl; aryl;heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl; halogen; aroyl,acyl; and aralkyl; any of said R² being optionally substituted with OH,SH, NH₂, oxo and halogen,

[0063] each n is independently selected from the group consisting of 0,1, 2 and 3; and

[0064] E is the aromatic ring system of any conventionalanti-inflammatory or analgesic agent.

[0065] More preferred compounds of formulas I and II are those wherein Aor B or both are independently selected from the group consisting of—(CR²R²)_(n)—O—CO—(CR²R²)_(n)-E , —(CR²R²)_(n)—CO—O—(CR²R²)_(n)-E,—(CR²R²)_(n)—O—CH(OH)—(CR²R²)_(n)-E and —(CR²R²)_(n)—O—(CR²R²)_(n)-E,wherein:

[0066] each R² is independently selected from the group consisting of H;alkyl; alkenyl; alknyl; alkoxy; aminoalkyl; haloalkyl; aryl;heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl; halogen; aroyl,acyl; and aralkyl; any of said R² being optionally substituted with OH,SH, NH₂, oxo and halogen,

[0067] each n is independently selected from the group consisting of 0,1, 2 and 3; and

[0068] E is selected from the group consisting of formulas III-VII:

[0069] wherein:

[0070] each R⁴ is independently selected from the group consisting of H,alkyl; alkenyl; alkynyl; acyl; aroyl; and halogen, said alkyl, alkenyl,alkynyl and carboalkyl being optionally substituted with OH, SH, NH₂,oxo and halogen; and

[0071] each R⁵ is independently selected from the group consisting ofalkyl; alkenyl; alkynyl; alkoxy; aminoalkyl; haloalkyl; aryl;heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl; halogen; aroyl,acyl; and aralkyl; any of said R⁵ being optionally substituted with OH,SH, NH₂, oxo and halogen.

[0072] In each of the more preferred compounds of formulas I and II(i.e., wherein E is selected from the group consisting of formulasIIl-VII), we particularly prefer those compounds wherein A is selectedfrom the group consisting of —CH₂—O—C(O)-E and —C(O)—O—CH₂-E and B isO—CO-Ph.

[0073] Most preferred compounds of formulas I and II are those havingthe structures of formulas VIII-XV:

[0074] The compounds of formulas VIII and IX are covalently coupledbenzoylecgonine-aspirin derivatives. The compounds of formulas X and XIare covalently coupled benzoylecgonine-ibuprofen derivatives. Thecompounds of formulas XII and XIII are covalently coupledbenzoylecgonine-benzoylecgonine derivatives. The compounds of formulasXIV and XV are covalently coupled benzoylecgonine-naproxen derivatives.

[0075] The compounds of formulas I and II (including the preferred, morepreferred and most preferred compounds listed above) are useful foralleviating the symptoms of immunoregulatory disorders, neuromusculardisorders, joint disorders, connective tissue disorders, circulatorydisorders and pain. As the skilled artisan will appreciate, mixtures oftwo or more compounds of formulas I and II will also be useful in anyapplication where a single compound of formula I and II is useful.

[0076] While not wishing to be bound by theory, we believe that thecompounds of this invention may act as prodrugs. We believe that underphysiological conditions, hydrolysis or other metabolic processes (suchas oxidation or O-dealkylation) slowly occur at the 2-β position ofcompounds of formulas I and II and possibly, at the 3-β position ofcompounds of formula I, resulting in the formation of the correspondingbenzoylecgonine, ecgonine and ecgonidine compounds. Also, if, as in thecases of the preferred compounds of this invention, the metabolicby-product is also a therapeutically active compound, one or moreadditional therapeutically active compounds are formed along with thecorresponding benzoylecgonine, ecgonine and ecgonidine compound.However, it should be noted that the compounds of this invention mayalso exhibit efficacy in their original, unhydrolyzed or unmetabilizedform.

[0077] In their unhydrolyzed or unmetabilized form, compounds offormulas I and II are more readily absorbed into the bloodstream thanthe corresponding benzoylecgonine, ecgonine and ecgonidine compoundsbecause of their increased lipophilicity. We believe that byderivatizing benzoylecgonine, ecgonine and ecgondine at the 2- and3-positions, the lipophilicity of these compounds is increased, whilethe desired properties of the corresponding benzoylecgonine, ecgonineand ecgonidine compounds are maintained or enhanced. By administeringthe compounds of this invention to a patient, greater amounts of theactive ingredient will enter the bloodstream and reach the targeted areathan if the benzoylecgonine, ecgonine and ecgonidine compoundsthemselves were administered at the same dosage level. Accordingly, thepharmaceutical effects of the benzoylecgonine, ecgonine and ecgonidinecompounds will be enhanced at a lower dosage level without additionalside effects.

[0078] In addition, when benzoylecgonine, ecgonine and ecgonidine arecovalently coupled with other known antiinflammatory or analgesicagents, those covalently coupled compounds will hydrolyze or otherwisebe metabolized in the body to produce two or more active compounds. Webelieve that once hydrolysis or other metabolic processes have occurred,the active compounds will exert a substantial synergistic effect. Thismechanism may also lead to better targeting of multiple therapeuticagents to a particular site (i.e., by delivering them together and byaltering the lipophilicity, polarity and other pharmacochemiucalcharacteristics of the covalently coupled molecule). This mechanism mayalso be used as a prolonged action form, whereby the covalently coupledactive compounds are slowly released in the body over a period of time.By delivering several active drugs in a single molecule, multiple-drugdelivery can be attained by single-dose therapy. This delivery systemshould result in a reduction of the side effects often associated withoral delivery of anti-inflammatory and analgesic agents. Importantly,gastrointestinal problems should be minimized because the majority ofthe hydrolytic and other metabolic processes that results in theformation of multiple active compounds occurs in the intestinal tract,not in the stomach.

[0079] The flexibility in the number and nature of the active componentscovalently linked in a single molecule is a unique feature of thisinvention. As described in formulas I and II above, one or two M or M′groups may be linked to the A and B positions in those molecules.Accordingly, one to four units of M or M′ may be released as a result ofhydrolysis. It should be noted that every one of the possible linkagepoints need not be hydrolyzable. For example, in a compound of formulaI, position A may be occupied by a hydrolyzable moiety (such as—O—CO—(CR²R²)_(n)-E, wherein R², n and E are defined as above forcompounds of formula I and II) while position B may be occupied by anon-hydrolyzable moiety (such as OH). In addition, two or morebenzoylecgonine, ecgonine and ecgonidine molecules may be linkedtogether (for example, see formulas XII and XIII above).

[0080] Furthermore, pharmacological effects which were previouslyunattainable using particular modes of administration (such as topicaladministration) can now be realized, due to the decrease in the requireddosage level. And because of their increased solubility in solution, theactual administered amount of a pharmaceutical composition containingthe compounds of this invention will be decreased, making thecomposition more easily applied and the treatment regimen moreacceptable to the patient. Consequently, it is possible to administereffectively the compounds of this invention in a wide variety of dosageforms.

[0081] In addition, the compounds of formulas I and II in theirunhydrolyzed or unmetabolized form are able to enter the central nervoussystem (“CNS”) in an amount effective to treat certain CNS disorders(such as, for example, Parkinson's disease), without causing adverseside effects commonly associated with conventional centrally-activedrugs (e.g., euphoria, tachycardia and vasoconstriction). We believethat in the prodrug form, the compounds of formulas I and II canpenetrate the blood/brain barrier and then be hydrolyzed to thecorresponding benzoylecgonine, ecgonine and ecgonidine compound (whichcould not have passed through the blood/brain barrier). In this manner,pharmaceutically effective amounts of benzoylecgonine, ecgonine andecgonidine compounds can be successfully targeted to the CNS.

[0082] We also believe that the compounds of formulas I and II in theirnative, unhydrolyzed or unmetabolized form may be useful in alleviatingthe symptoms of the aforementioned disorders without subsequentformation of the benzoylecgonine, ecgonine and ecgonidine compounds viahydrolysis or other metabolic processes. Compounds of formulas I and IImay, for example, act peripherally to improve circulation to theafflicted areas. In addition, by increasing the levels of peripherallycirculating dopamine (for example, by preventing dopamine re-uptake atthe synaptosome), the compounds of this invention may create a chemicalsympathectomy.

[0083] Although the precise mode of action of the compounds of thisinvention is not known, one theory is that the compounds of formulas Iand II undergo a chelation reaction with the fibers of the muscles andjoint capsules, allowing the fibers of the connective tissue to relaxand become elongated. This elongation of the connective tissue fiberswould result in decreased inflammation by increasing circulation andmuscle activity and by improving joint motion. This theory explains thepositive therapeutic results experienced by patients having joint,neuromuscular, connective tissue and circulatory disorders.

[0084] Alternatively, the compounds of formulas I and II may act aschelating agents of certain neurotransmitters or co-factors in the body(such as, for example, calcium, sodium and potassium ions). The bloodlevel of free neurotransmitters and co-factors has a direct effect onthe functioning of ionic channels and consequently, on intracellularresponse to various stimuli (such as, for example, intracellularmediation of catecholamine response through the cAMP system). Therefore,the formation of chelation complexes may play a significant role in thepharmacological activity of the compounds of this invention. Under thesechelation theories, the substitution of a highly polar or hydrogenbonding moiety in one or more L, L′, M and M′ located in positions A andB (such as a hydroxyl, thiol, amino or halogen substitutions) isparticularly preferred.

[0085] Another alternative theory involves the intracellular degradationof the compounds of this invention, resulting in the production ofcertain analgesic, anti-oxidant and anti-inflammatory compounds (such asbenzoic acid and salicylic acid). The in vivo production of suchpharmaceutically active compounds would procure the benefit of thoseagents while avoiding many of the side effects associated with theiradministration (such as gastrointestinal and renal toxicity). The invivo production of anti-oxidants might explain the impressiveimmunoregulatory effects shown by the compounds of this invention.Likewise, the production of analgesics and anti-inflammatory agents inthe body would also help to explain the mode of action of the compoundsof this invention in alleviating pain.

[0086] Another possible mode of action involves a reduction inprostaglandin synthesis by inhibiting the action of phospholipase.During conditions of inflammation, pain, fever and platelet aggregation,arachidonic acid is liberated from phospholipid fractions of cellmembranes by phospholipase A2. The arachidonic acid is then converted toother products, such as intermediate cyclic endoperoxide prostaglandins.These intermediates produce pain, inflammation and vasoconstriction.Prostaglandins have many other biological actions, including the abilityto produce erythema, edema, pain, fever, vasodilation and uterinecontractions. Therefore, by inhibiting the synthesis of prostaglandins,many desired physical effects can be realized.

[0087] Other possible modes of action include inhibition of chemotaxisof cells implicated in the inflammatory process, inhibition of lysosomalmembrane labilization, antagonistic effects on mediators other thanprostaglandins (e.g., histamines and bradykinin), inhibition of thebiosynthesis of mucopolysaccharides, uncoupling of oxidativephosphorylation, fibrinolytic activity and sulfhydryl-disulfidestabilization.

[0088] The compounds of this invention may be easily synthesized usingknown techniques. Compounds of formulas I and II having L or L′ as areversed ester linkage (i.e., —C(O)—O—) may be prepared from ecgonine orbenzoylecgonine compounds by simple esterification of the free acid withthe alcohol form of any desired M or M′ moiety. Compounds of formulas Iand II having L or L′ as acetal or hemiacetal linkers can also beprepared using known techniques. Typically, the free acid form ofbenzoylecgonine, ecgonine or ecgonidine compounds may be reduced to thecorresponding alcohol. One mole of alcohol may then be reacted with onemole of the aldehyde or ketone form of the desired M or M′ moiety toform a hemiacetal. Alternatively, two moles of alcohol may be reactedwith one mole of the aldehyde or ketone form of the desired M or M′moiety to form an acetal. Similarly, the desired M or M′ moiety may beconverted to a corresponding alcohol, then reacted with the free acidform of benzoylecgonine, ecgonine or ecgonidine compounds to yieldhemiacetals or acetals.

[0089] Compounds of formulas I and II having L or L′ as ester linkages(i.e., (—O—C(O)—) may be readily prepared from the reduction of the freeacid form of benzoylecgonine, ecgonine and ecgonidine compounds to thealcohol, followed by esterification of the free acid form of the desiredM or M′ moiety. Many of these techniques are described in A. H. Lewin etal., “2β-Substituted Analogues of Cocaine. Synthesis and Binding to theCocaine Receptor”, J. Med. Chem., 35, pp. 135-40 (1992). It is wellwithin the skill of the art to devise and carry out such reactionschemes.

[0090] As can be appreciated by a chemist of ordinary skill in the art,the simple synthetic schemes described above can be modified to produceany of the compounds of formulas I and II. Such modifications mightinvolve alterations in the starting materials or the addition of furthersynthetic steps (such as functional group transformations). Depending onprecisely how the synthetic scheme is modified, the specific reactionconditions (such as the precise temperature and reaction times) mightalso require modification. Since the progress of these reactions can beeasily monitored by techniques such as high performance liquidchromatography, gas chromatography, mass spectroscopy, thin layerchromatography, nuclear magnetic resonance spectroscopy and the like,such modifications are well within the skill of the art.

[0091] The compounds of this invention, and mixtures thereof, may beadministered alone or in combination with other compounds, such as, forexample, benzoylecgonine, ecgonine and ecgonidine compounds. When acompound of formula I or II, or a mixture thereof, is administeredtogether with benzoylecgonine, ecgonine or ecgonidine, the therapeuticefficacy of the latter compounds may be enhanced. We prefer thatpharmaceutical compositions comprising a compound of this invention, ora mixture thereof, in combination with benzoylecgonine, ecgonine and/orecgonidine contain at least 5%, but more preferably at least 10%, of thecompound or compounds of formulas I and II (w/w). We also preferpharmaceutical compositions of this invention, and the mixturescontained therein, wherein no more than 0.1% cocaine (w/w) is present.

[0092] This invention also envisions the administration of the compoundsof formulas I and II in combination with conventional therapeuticagents. Advantageously, such combination therapies utilize lower dosagesof those conventional therapeutics, thus avoiding possible toxicity andadverse side effects incurred when those agents are used asmonotherapies. For example, the compounds of this invention may be usedin combination with conventional cancer drugs (such as, for example,methotrexate, taxol, 5-fluorouracil, cis-platinum, cortisone, nitrogenmustards, thiotepa and nitrosoureas), arthritis drugs (such as, forexample, non-steroidal anti-inflammatory agents, penicillamine,methotrexate, cortisone and gold salts) and neurological agents (suchas, for example, amantadine, L-DOPA and CNS-anticholinergics).

[0093] According to this invention, the compounds of formulas I and II,or mixtures thereof, and the pharmaceutical compositions containingthose compounds, may be administered to any mammal, including a human.The compounds and pharmaceutical compositions of this invention may beadministered in any pharmaceutically acceptable dosage form, including,but not limited to intravenously, intramuscularly, subcutaneously,intra-articularly, intrasynovially, intrathecally, periostally,intratumorally, peritumorally, intralesionally, perilesionally, byinfusion, sublingually, buccally, transdermally, orally, topically or byinhalation. We prefer oral, topical and transdermal administration andadministration by inhalation.

[0094] Dosage forms may include pharmaceutically acceptable carriers andadjuvants which are known to those of skill in the art. These carriersand adjuvants include, for example, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances and polyethylene glycol. Adjuvants fortopical or gel base forms of the compounds and compositions of thisinvention include, but are not limited to, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyoxyethylene-polyoxypropylene-block polymers, polyethylene glycol,propylene glycol and wool fat. For topical applications, we prefer touse propylene glycol.

[0095] For all administrations, conventionally administered dosage formsmay be used. Such forms include, for example, tablet, capsule, caplet,liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutablepowder, granule, suppository and transdermal patch. Methods forpreparing such dosage forms are known (see, for example, H. C. Ansel andN. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems,5th edition, Lea and Febiger 1990).

[0096] The compounds and pharmaceutical compositions of this inventionmay be employed in a conventional manner to alleviate the symptoms ofany of the aforementioned disorders (i.e., by administration to amammal, including a human, a pharmaceutically effective amount of apharmaceutical composition of this invention). Such methods and theirdosage levels and requirements are well-recognized in the art and may bechosen by those of ordinary skill in the art from the available methodsand techniques. Typically, dosage levels range from about 25-200 mg/dosefor a 70 kg patient. Although one dose per day is often sufficient, upto 5 doses/day may be given. For oral doses, up to 1500 mg/day may berequired. A typical treatment regimen for a 70 kg patient with a jointdisorder (such as rheumatoid arthritis) or an immunoregulatory disorder(such as an autoimmune disease) is four doses/day (200 mg/dose),topically applied for two weeks. However, some disorders (such asosteoarthritis) require only 1 dose/day for two days. Once the symptomsof the disorder have receded, maintenance doses can be administered on ap.r.n. basis. As the skilled artisan will appreciate, lower or higherdoses than those recited above may be required. Specific dosage andtreatment regimens will depend on such factors as the patient's generalhealth status, the severity and course of the patient's disorder ordisposition thereto and the judgment of the treating physician.

[0097] Immunoregulatory disorders that may be treated with the compoundsand compositions of this invention include, but are not limited to:inflammation, autoimmune diseases, allergies (such as, for example,insect bites and stings (e.g., mosquito, fire ant, bee or fly), poisonivy, poison oak and contact dermatitis.

[0098] Neuromuscular disorders that may be treated with the compoundsand compositions of this invention include, but are not limited to:amyotrophic lateral sclerosis, multiple sclerosis, skeletal muscletrauma, spasm post-stroke, loss of sensory acuity, weakness, cerebraledema, Reiter's syndrome, polymyositis, Parkinson's disease,Huntington's disease, angina and acute back strain.

[0099] Joint disorders that may be treated with the compounds andcompositions of this invention include, but are not limited to: frozenshoulder, restricted range of motion, post-fracture contracture,arthritis (such as, for example, rheumatoid arthritis, osteoarthritis,mixed arthritis, psoriatic arthritis, gout, inflammatory gout orjuvenile rheumatoid arthritis), bursitis, ankylosing spondylitis,rheumatoid vasculitis and joint rigidity.

[0100] Connective tissue disorders that may be treated with thecompounds and compositions of this invention include, but are notlimited to: systemic lupus, Burger's disease, periarteritis nodosum,proliferative diseases (e.g., keloid scar formation, excessive scarformations, sanctity of scarified fibers and proliferative cancers suchas carcinomas and sarcomas), scieroderma and collagen disorders.

[0101] Circulatory disorders that may be treated with the compounds andcompositions of this invention include, but are not limited to: anginapectoris, myocardial ischemia, gangrene and diabetes (such as diabetesmellitus and diabetes insipidus).

[0102] We believe that the compounds and compositions of this inventionare especially well suited for use in alleviating pain and alleviatingthe symptoms of inflammation, Parkinson's disease, acute back strain,restricted range of motion, arthritis, bursitis, ankylosing spondylitis,Burger's disease and myocardial ischemia.

[0103] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any way.

CHEMICAL SYNTHESES

[0104] In the following examples, these instruments and procedures areused:

[0105] GC/MS analyses are performed on a Finnigan Model 9610 gaschromatograph-4000 Mass Spectrometer equipped with an IBM-AT computerusing Teknivent Vector/one data system software (St. Louis, Mo.). Themass spectrometer is calibrated using perfluorotributylamine.Chromatographic separations are achieved on a 30 mm×0.32 mm, 0.25 μmfilm thickness dimethysilicone fused silica capillary column (BD-1, J&WScientific, Folson, Calif.). Ultra pure helium is used as the carriergas and compressed air is used as the make up gas (Sunox Inc.,Charleston, S.C.).

[0106] Reagents and samples are weighed on a microbalance type 2406(range 0-20 g, Sartorius Werke GMBH Gottigen, Germany), microbalancetype 4503 (range 0-1 g, Sartorius Werke GMBH (Gottingen, Germany), or amicrobalance type 2842 (range 0-160 g, Sartorius Werke GMBH Gottigen,Germany).

[0107] A Vortex-Genie (Scientific Industries, Inc. Bohemia, N.Y.) isused to mix standards. A Varian Aerograph series 1400 gaschromatographic oven is used to heat all samples requiringderivatization. A Fisher Isotem 500 series drying oven is used fordrying glassware.

[0108] Three necked round bottomed flasks (250 ml, 50 ml, 100 ml and 500ml) are used for synthesis. Centrifuge tubes (15 ml) are silanized witha solution of dimethyldichlorosilane in toluene. Disposable borosilicatepipettes (1, 5, and 10 ml) by Fisher Scientific Company are used.Derivatizing reactions are carried out using teflon lined 1, 2, and 3dram vials. All other glassware is routine scientific glassware forsynthetic or analytical purposes. The HPLC analyses are performed withan HPLC system which consisted of a Beckman M-45 delivery pump, ModelLambda Max 481 LC spectrophotometer variable wavelength UV absorbancedetector equipped with an automatic sampling Wisp injector model 710Baccessory and a Shimadzu C-R3A Chromatopac integrator. The stationaryphase is a reversed phase C18 column (μm Bondapak of Millipore, P/N27324, (3.9 mm ID×30 cm).

[0109] Thin layer chromatography (TLC) is performed on Whatman silicagel 60 TLC plates.

[0110] All HPLC analyses are performed with the UV detector operating at232 wavelength. The mobile phase is 20% v/v acetonitrile in 0.01 M KHPO₄(pH range 2.1-2.9) with a flow rate of 2.0 ml/min. The injection volumeis 15 μl and operating range as 0.1 AUFS. No internal standard isutilized for HPLC.

[0111] A filter holder (Fisher brand) assembly with a 300 ml fritglasssupport (47 mm) is used to degas the HPLC mobile phase. Filter papers(0.22μ, Lazar Scientific, Los Angeles, Calif.) are used to filter themobile phase for the HPLC assay.

[0112] Homatropine hydrobromide, pentafluoro-propionic anhydride (PFPA),and pentafluoropropanol (PFP) are obtained from Aldrich Chemical Co.(Milwaukee, Wis.).

[0113] A high line vacuum is used to evaporate or distill propyleneglycol solution.

[0114] Solvents from derivatization are removed by evaporating (withevaporating needles) under a stream of nitrogen. Solvents requiring heatduring evaporation are heated in a sand bath.

[0115] All mass spectrometric analyses utilize the Finnigan system. Thehelium gas linear velocity is at 50 cm/s. The data system scan rate isevery 0.2 s with a sweep width of 0.1μ, integrating each acquisitionsample for 4 ms. Perfluorotributylamine is used to calibrate the MS.Electron impact ionizing voltage is at 60 eV and ionizing current at 300μA. The electron multiplier is operated at 1700 V. With injection portand MX ion source temperature set at 250° C. and 260° C., respectively,separation is achieved using a multi-linear programmed temperatureinitially at 130° C. and increased to 140° C. at 20°/ min, then finallyto 258° C. at 17°/min. When isothermal conditions are used, the columntemperature is maintained at 160° C., 185° C., 200° C., or 220° C. For atypical analytical procedure, 0.05 μl or 0.1 μl with an equal amount ofair is quickly injected into the GC injection port. Upon injection ofthe sample, temperature programming begins, acquisition ismonitored, andthe filament is activated 1.5 min after injection of sample.

[0116] Derivatization of the compounds is performed before GC/MSanalysis. 10 μl of the compound to be derivatized is placed in a tefloncapped vial and derivatized with the 35 μl volume of PFP and 70 μl PFPA.The vial is heated at 100° C. for 20 min, cooled, excess reagentsevaporated, reconstituted with acetonitrile to the desired volume, andthen analyzed on GC/MS.

[0117] Cocaine base is prepared by the following protocol: Cocaine HCl(5.0 g) is dissolved in 150 ml of distilled water. Volumes of 1N KOH areadded with stirring to a final pH of about 10. The white solid formed ispadded dry using filter paper and paper towel. The solid is then placedin a 500 ml beaker and allowed to melt in a 100° C. to 110° C. oil bath.Once the solid is completely melted, the beaker is removed and allowedto cool to room temperature. The excess water is decanted and thecrystallized cocaine base allowed to air dry.

[0118] Benzoylecgonine is synthesized by the following protocol: Cocainebase (9.3 g) is mixed with 200 ml of distilled water and allowed toreflux for 5 hr. The resultant solution is cooled and extracted fivetimes with diethyl ether. The aqueous layer is evaporated under reducedpressure and the residue is recrystallized from water. Needle shapedwhite crystals are collected (approximate yield: 50%).

[0119] Ecgonine HCl is synthesized by direct acid hydrolysis of cocaineusing the protocol described in M. R. Bell and S. Archer,“L(+)-2-Tropinone”, J. Amer. Chem. Soc., 82, pp. 4642-44 (1960): CocaineHCl (9.0 g) is dissolved in 10 ml of 12 N HCl and 150 ml of distilledwater and refluxed for 15 hr. The resultant solution is cooled andextracted five times with diethyl ether, the aqueous phase is combinedand evaporated under reduced pressure. The residue is recrystallizedfrom ethanol and water to yield white crystals (approximate yield: 50%).

[0120] Structure elucidation is performed by GC/MS and confirmed by theobserved retention times of the fluorinated derivatives and the observedMS fingerprint fragment ions.

[0121] Benzoylecgonine is reduced to the corresponding alcohol (i.e.,3β-(benzoyloxy)-2β-(hydroxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane)using the following protocol:

[0122] To a stirred suspension of benzoylecgonine (1.45 g, 5 mmol) infreshly distilled THF (75 ml) at 0° C. is added dropwise diborane-THFcomplex (18 ml, 18 mmol) over a period of 15 minutes. After stirring at0° C. for another 2 hour and then at room temperature for 1 hour, excessdiborane is carefully destroyed by the addition of MeOH. The mixture isacidified to pH 1 with 6N HCl and concentrated by evaporation. Thesolution is then basified with 6N NH₄OH and extracted with CH₂Cl₂. Theconcentrated extract is dried (over Na₂SO₄) and evaporated. The residueis purified by thin-layer chromatography eluting with 10% MeOH/CH₂Cl₂.The fractions containing the product are pooled, evaporated andcrystallized from CH₂Cl₂/petroleum ether (approximate yield: 30%). Inthe examples that follow, this product is referred to as BEc(OH).

EXAMPLE 1 Synthesis of Compound VIII

[0123] To a stirred solution of BEc(OH) (155 mg, 0.55 mmol) and Et₃N(0.2 ml, 1.4 mmol) in CH₂Cl₂ (5 ml) at room temperature is addeddropwise a solution of 2-[acetoxy]-benzoic acid chloride (1.2 mmol) inCH₂Cl₂. After 3 hours, the mixture is treated with H₂O (2 ml). Theorganic phase is separated and the aqueous phase is extracted withCH₂Cl₂ (2×5 ml). The combined organic extract is washed with H₂O anddried over Na₂SO₄. Removal of the solvent yields compound VIII.

EXAMPLE 2 Synthesis of Compound X

[0124] The following synthetic scheme was employed to produce compoundX:

[0125] In this example, BEc(OH) was produced by dissolvingbenzoylecgonine (1.00 g, 3.5 mmol) in a minimum amount of dry ACN in a50 ml Erlenmeyer flask fitted with a magnetic stirrer and rubber septum.The mixture was placed in an ice bath at 0° C. under N₂ and 1.0 Mdiborane-THF (12.5 ml) was added slowly over 6-10 minutes via syringe.The solution was stirred at 0° C. for two hours, then allowed to come toroom temperature and stirred overnight. Excess diborane was destroyed bycareful addition of MEOH. The solution was concentrated by evaporationunder reduced pressure and the residue made acidic to litmus by theaddition of 6N HCl. The mixture was then evaporated to dryness underreduced pressure and allowed to cool to room temperature. The solutionwas made basic to litmus with 6N NH₄OH and extracted into CH₂Cl₂. Theorganic layer was dried over Na₂SO₄; filtered and evaporated to dryness.GC/MS showed analytically pure alcohol product (tan solid, 934.8 mg,98.2% yield).

[0126] Methyl trifluoromethane sulfonate (CH₃OTf) (0.02 ml, 0.18 mmol)was added dropwise to a cooled solution (ice water bath) ofcarbonyldiimidazole (CMBI) (30.8 mg, 0.20 mmol) in 10 ml redistillednitromethane (CH₃NO₂) contained in a 50 ml Erlenmeyer flask fitted witha magnetic stirrer. This solution was added dropwise over six to tenminutes to a suspension of ibuprofen (117.4 mg, 0.57 mmol), in 10 mlCH₃NO₂ in a 50 ml round bottomed flask fitted with a condensing columnand a magnetic stirrer. After five minutes, BEc(OH) (49.0 mg, 0.18 mmol) was added. The reaction mixture was refluxed under N₂. GC/MS performedafter 2 hours detected no residual BEcOH. After allowing the reaction torun overnight, no change was seen in the GC/MS profile. The reactionmixture was allowed to come to room temperature, then quenched with 5 mlwater and extracted into diethyl ether. The ether extract was washed 2times with equal portions of saturated NaHCO₃ and 2 times with equalvolumes of brine. The organic layer was dried over Na₂SO₄, filtered andallowed to evaporate under the hood.

[0127] Solid probe GC/MS showed results consistent with a singlecomponent sample corresponding to the expected product, compound X(amber oil, 70.1 mg, 83% crude yield).

[0128]¹H NMR: δ, 0.9 (d, 6H); 1.5 (d, 3H); 2.4 (d, 2H); 4.1 (dq, 3H);7.2 (m, 2H); 7.6 (m, 2H).

[0129] MS: m/z=465 (molecular ion)

[0130] 206 (ibuprofen)

[0131] 275 (BEc)

[0132] 105, 77, 121, 300 (tropane)

EXAMPLE 3 Synthesis of Compound XIII

[0133] To a stirred solution of BEc(OH) (155 mg, 0.55 mmol) and Et₃N(0.2 ml, 1.4 mmol) in CH₂Cl₂ (5 ml) at room temperature is addeddropwise a solution of the acid chloride of benzoylecgonine (1.2 mmol)in CH₂Cl₂. After 3 hours, the mixture is treated with H₂O (2 ml). Theorganic phase is separated and the aqueous phase is extracted withCH₂Cl₂ (2×5 ml). The combined organic extract is washed with H₂O anddried over Na₂SO₄. Removal of the solvent yields compound XIII.

EXAMPLE 4 Synthesis of Compound XV

[0134] To a stirred solution of BEc(OH) (155 mg, 0.55 mmol) and Et₃N(0.2 ml, 1.4 mmol) in CH₂Cl₂ (5 ml) at room temperature is addeddropwise a solution of 2-methyl-2-[6-methoxy-2-naphthyl]-acetic acidchloride (1.2 mmol) in CH₂Cl₂. After 3 hours, the mixture is treatedwith H₂O (2 ml). The organic phase is separated and the aqueous phase isextracted with CH₂Cl₂ (2×5 ml). The combined organic extract is washedwith H₂O and dried over Na₂SO₄. Removal of the solvent yields compoundXV.

[0135] While we have described a number of embodiments of thisinvention, it is apparent that our constructions may be altered toprovide other embodiments which utilize the basic teachings of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims, rather than by thespecific embodiments which have been presented by way of example.

What is claimed is:
 1. A compound of formula I or II:

wherein: each R¹ is independently selected from the group consisting ofH; COR²; COBn, alkyl; alkenyl; and alkynyl, said alkyl, alkenyl andalkynyl being optionally substituted with OH, SH, NH₂, CN, CF₃ orhalogen; A is -L—(M)p; B is -L—(M′)p′; each p and p′ is independentlyselected from the group consisting of 1 or 2; each L is independently alinker which, (a) if linking one M or M′ to the ring system, is selectedfrom the group consisting of —(CR²R²)_(n)—CO—Q—; —(CR²R²)_(n)—Q—CO—;—(CR²R²)_(n)—O—C(OH)—; and —(CR²R²)_(n)—Q—; or (b) if linking two M orM′, the same or different, to the ring system is

(c) if linking two ring systems chosen from compounds of formulas I andll, the same or different, to M or M′ is

each n is independently selected from the group consisting of 0, 1, 2and 3; each Q is independently selected from the group consisting of—NH—, —O— and —S—; each M and M′ is independently a moiety that, eitheralone or in combination with other M or M′ moieties, enhance thedistribution characteristics, intrinsic activity or efficacy of saidcompound, provided that M is not a moiety having the formula —CH₂—CHX—R³when B is —O—CO—M′, —O—M′ or when B is not present (i.e., in compoundsof formula II); each R² is independently selected from the groupconsisting of H; alkyl; alkenyl; alkynyl; alkoxy; aminoalkyl; haloalkyl;aryl; heterocyclyl; aralkyl, cycloalkyl; cycloalkylallkyl; halogen;aroyl, acyl; and aralkyl; any of said R² being optionally substitutedwith OH, SH, NH₂, oxo and halogen; X is selected from the groupconsisting of OH; SH; NH₂; and halogen; and R³ is selected from thegroup consisting of alkyl, alkenyl and alkynyl, optionally substitutedwith OH, SH, NH₂ or halogen; COCH₃; COPh; and COBn.
 2. The compoundaccording to claim 1, wherein Q is —O—; M′ is selected from the groupconsisting of —OH, O—(CH₂)_(n)-aryl and O—C(O)-aryl; and n is selectedfrom the group consisting of 0 and
 1. 3. The compound according to claim1, wherein A or B or both are independently selected from the groupconsisting of —(CR²R²)_(n)—O—CO—(CR²R²)_(n)-E ,—(CR²R²)_(n)—CO—O—(CR²R²)_(n)-E, —(CR²R²)_(n)—O—CH(OH)—(CR²R²)_(n)-E and—(CR²R²)_(n)—O—(CR²R²)_(n)-E, wherein: each R² is independently selectedfrom the group consisting of H; alkyl; alkenyl; alkynyl; alkoxy;aminoalkyl; haloalkyl; aryl; heterocyclyl; aralkyl; cycloalkyl;cycloalkylalkyl; halogen; aroyl, acyl; and aralkyl; any of said R² beingoptionally substituted with OH, SH, NH₂, oxo and halogen, each n isindependently selected from the group consisting of 0, 1, 2 and 3; and Eis the aromatic ring system of any conventional anti-inflammatory oranalgesic agent.
 4. The compound according to claim 3, wherein E isselected from the group consisting of formulas III-VII:

wherein: each R⁴ is independently selected from the group consisting ofH, alkyl; alkenyl; alkynyl; acyl; aroyl; and halogen, said alkyl,alkenyl, alkynyl and carboalkyl being optionally substituted with OH,SH, NH₂, oxo and halogen; and each R⁵ is independently selected from thegroup consisting of alkyl; alkenyl; alkynyl; alkoxy; aminoalkyl;haloalkyl; aryl; heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl;halogen; aroyl, acyl; and aralkyl; any of said R⁵ being optionallysubstituted with OH, SH, NH₂, oxo and halogen.
 5. The compound accordingto claim 3 or 4, wherein A is selected from the group consisting of—CH₂—O—C(O)-E and —C(O)—O—CH₂-E and B is O—CO-Ph.
 6. A compound havingthe structure of any one of formulas VIII-XV:


7. A pharmaceutical composition comprising a compound according to anyone of claims 1-6, or a mixture thereof, and a pharmaceuticallyacceptable carrier or adjuvant.
 8. The pharmaceutical compositionaccording to claim 7, further comprising at least one additionalingredient selected from the group consisting of benzoylecgonine,ecgonine and ecgonidine.
 9. The pharmaceutical composition according toclaim 7 or 8, wherein the composition comprises at least about 5% of thecompound according to any one of claims 1-6, or a mixture thereof 10.The pharmaceutical composition according to claim 7 or 8, furthercomprising at least one additional ingredient selected from the groupconsisting of methotrexate, taxol, 5-fluorouracil, cis-platinum,cortisone, nitrogen mustards, thiotepa and nitrosoureas, non-steroidalanti-inflammatory agents, penicillamine, methotrexate, cortisone andgold salts, amantadine, L-DOPA and CNS-anticholinergics.
 11. Thepharmaceutical composition according to claim 7 or 8, wherein thecomposition is in an administering dosage form selected from the groupconsisting of a tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch.
 12. A method for alleviating the symptoms ofimmunoregulatory disorders, neuromuscular disorders, joint disorders,connective tissue disorders, circulatory disorders or pain, comprisingthe step of administering to a mammal, including a human, apharmaceutically effective amount of the pharmaceutical compositionaccording to claim 7 or
 8. 13. The method according to claim 12, whereinthe pharmaceutical composition is administered intravenously,intramuscularly, subcutaneously, intra-articularly, intrasynovially,intrathecally, periostally, intratumorally, peritumorally,intralesionally, perilesionally, by infusion, sublingually, buccally,transdermally, orally, topically or by inhalation.
 14. The methodaccording to claim 12 or 13, wherein the disorder is selected from thegroup consisting of pain, inflammation, autoimmune diseases, allergies,poison ivy, poison oak, contact dermatitis, amyotrophic lateralsclerosis, multiple sclerosis, skeletal muscle trauma, spasmpost-stroke, loss of sensory acuity, weakness, cerebral edema, Reiter'ssyndrome, polymyositis, Parkinson's disease, Huntington's disease,angina, acute back strain, frozen shoulder, restricted range of motion,post-fracture contracture, arthritis, bursitis, ankylosing spondylitis,rheumatoid vasculitis, joint rigidity, osteoarthritis, mixed arthritis,psoriatic arthritis, gout, inflammatory gout, juvenile rheumatoidarthritis, systemic lupus, Burger's disease, periarteritis nodosum,proliferative diseases, scleroderma, collagen disorders, anginapectoris, myocardial ischemia, gangrene and diabetes.
 15. The methodaccording to claim 14, wherein the disorder is pain, inflammation,Parkinson's disease, acute back strain, restricted range of motion,arthritis, bursitis, ankylosing spondylitis, Burger's disease andmyocardial ischemia.
 16. The use of the pharmaceutical compositionaccording to claim 7 or 8 for alleviating the symptoms ofimmunoregulatory disorders, neuromuscular disorders, joint disorders,connective tissue disorders, circulatory disorders or pain.
 17. The useaccording to claim 16, wherein the disorder is selected from the groupconsisting of inflammation, autoimmune diseases, allergies, poison ivy,poison oak, contact dermatitis, amyotrophic lateral sclerosis, multiplesclerosis, skeletal muscle trauma, spasm post-stroke, loss of sensoryacuity, weakness, cerebral edema, Reiter's syndrome, polymyositis,Parkinson's disease, Huntington's disease, angina, acute back strain,frozen shoulder, restricted range of motion, post-fracture contracture,arthritis, bursitis, ankylosing spondylitis, rheumatoid vasculitis,joint rigidity, osteoarthritis, mixed arthritis, psoriatic arthritis,gout, inflammatory gout, juvenile rheumatoid arthritis, systemic lupus,Burger's disease, periarteritis nodosum, proliferative diseases,scleroderma, collagen disorders, angina pectoris, myocardial ischemia,gangrene and diabetes.
 18. The use according to claim 17, wherein thedisorder is inflammation, Parkinson's disease, acute back strain,restricted range of motion, arthritis, bursitis, ankylosing spondylitis,Burger's disease and myocardial ischemia.